104. Acid-based etc In D´Mello handbook 2011

382 ©CAB International 2011. Amino Acids in Human Nutrition and Health (ed. J.P.F. D’Mello)

22.1 Abstract

Industrial processing of food has not only improved the management and safety of foods, but also its taste. Unfortunately how-ever, most of these processes – including plant breeding, gene manipulation, fraction-ation, separation, condensation, drying, freezing, heating, irradiation, roasting, micro-waving, toasting, smoking, emulsification, and homogenization – appear to be negative, as they reduce the nutritional quality of the food and also contribute significantly to increased vulnerability to development of diseases, especially those referred to as endemic and chronic.

This chapter deals especially with the negative consequences of heating and mainly with the impact of heat-produced glycated and lipoxidated molecules, often referred to as Maillard products. These products are more specifically referred to as advanced glycation end-products (AGE) and advanced lipoxidation end-products (ALE). The negative effects on health of other heat-produced compounds, such as heterocyclic aromatic amines, are outside the scope of this review.

Modern molecular biology has made it possible to explore the impact of these and other process-induced molecules on the body and its functions. The detection in 1992 of a specific receptor in the body for such prod-ucts provided the opportunity for a better understanding of their effects in health and disease. This receptor for advanced glycation end products (RAGE) is recognized as a key member of the immunoglobulin superfamily of cell surface molecules. It functions as a master switch, induces sustained activation of NF-kB, suppresses a series of endogenous autoregulatory functions, and converts long-lasting pro-inflammatory signals into sus-tained cellular dysfunction and disease. Its activation is associated with much increased levels of dysfunctioning proteins in body flu-ids and tissues, and is strongly associated with a series of diseases from allergy and Alzheimer’s disease to rheumatoid arthritis and urogenital disorders. It is important to observe that heat treatment and other forms of processing of foods will dramatically increase the content of these dysfunctional molecules, and thereby, with time, signifi-cantly contribute to the epidemic of chronic diseases seen around the world. An increased

22 Modified Amino Acid-Based Molecules: Accumulation and Health Implications

S. Bengmark*Division of Surgery and Interventional Science, University College London, London, UK

* E-mail address: [email protected]

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consumption of raw foods, fruits, and vegeta-bles; foods rich in polyphenols and other anti-oxidants; as well as live bacteria, probiotics, and plant fibre seems appropriate in order to counteract these undesirable developments.

22.2 Introduction

Modern food is often extensively processed prior to distribution and sale. Drying, freez-ing, heating, irradiation, roasting, microwav-ing, toasting, emulsifying, homogenizing, and the addition of numerous compounds are all aimed at enhancing the appeal of the food, its palatability, and its shelf-life. The effects of each of these manipulations on human health are not fully explored, and even when documented, often not considered to the extent they should be, either by indus-try or the consumer.

Heating food to higher temperatures is generally regarded to improve both the taste and smell of the foods we eat. High tempera-ture makes food proteins change structure: coagulate, aggregate, and produce crusts. Modern food chemists, chefs, and cooks use this information every day to produce deli-cious new foods.

The French biochemist Louis-Camille Maillard described the chemical process which occurs non-enzymatically in foods (Maillard, 1912), and which is much acceler-ated by heating. This process is now referred to as the Maillard reaction and its products collectively named Maillard products. Reducing sugars (fructose, glucose, glyceral-dehyde, lactose, arabinose, and maltose) will during the process bind to amino acids, nucleic acids, including DNA, RNA, pep-tides, and proteins, to produce transitional compounds, most often referred to as Amadori products. In time these undergo complex changes: cyclization, dehydration, oxidation, condensation, cross-linking, and polymerization, to form irreversible chemical products. In particular, reactive carbonyls such as glyoxal and methylglyoxal have been found to rapidly modify reactive side chains of proteins. Important amino acids such as lysine (essential amino acid) and histidine (essential for children) are often involved.

During the process significant amounts of pigments (melanoids) but also thousands of often good-tasting and good-smelling so-called volatile compounds will be released. These pigments often make the food or parts of the food look brown or black, which is why the process is sometimes referred to as ‘browning’. Common browning products are bread crusts and roasted surfaces of fried meat and fish, all sorts of broths, irrespective of vegetable or animal origin, and all smoked food, as well as Asian sauces, balsamic prod-ucts, Chinese soy, and cola products, all rich in brown/black Maillard products. But not all Maillard products are dark in colour; there are also white Maillard products, especially dairy products such as cheese and powdered milk. Maillard himself suggested that the Maillard process might be negative to health, as these products will accumulate in the body, as we now know, for many years and some-times for the rest of life. The process might also reduce the availability in the body of important and essential amino acids.

22.3 Effects of Heating on Food Quality

Heat-induced alterations of foods are consid-ered to commence at around 28°C – the highest processing temperature allowed for olive oil to be called virgin. Most enzymes in foods become deactivated after approximately 42°C. Some antioxidants are resistant to heat but a majority will disappear in the interval 30°–100°C, and almost all during microwaving. The heat-enhanced production of Maillard products – glycated and lipoxidated molecules – is said to start and accelerate from around 80°C. Similarly the heat-induced production of carcinogens such as heterocyclic amines is said to start from the interval 100°–130°C, after which the pro-duction accelerates dramatically.

Maillard products based on association of carbonyl groups in sugars and proteins are collectively referred to as AGE. Similar products, formed between reactive fatty acids and proteins, are referred to as ALE. Numerous such synthetic products are now identified, but two or three previously unknown compounds are each year added to the list. The most commonly studied AGE


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are pentosidine, Ne-carboxymethyl-lysine (CML), and Ne-(carboxyethyl)lysine (CEL).

It is important to note that the production of both AGE and ALE are not dependent on enzymes. The intensity in their production increases, not only with increase in tempera-ture, but also with length of storage at elevated temperatures, and even at room temperature. The content of the AGE furosine increases dramatically with heat treatment such as pasteurization and especially with the produc-tion and storage of powdered milk (Baptista and Carvalho, 2004). Other industrial practices commonly used in food processing such as irra-diation, ionization, microwaving, and smoking also contribute significantly to increased pro-duction of AGE/ALE. Vegetable-based foods are no exception – industrial treatment of plant products, such as roasting, drying, and ‘curing’ will lead to amounts of AGE/ALE that are as great as those found in animal products. One such example is roasted peanuts.

Fresh tobacco leaves, fresh coffee beans, and fresh peanuts are rich in powerful anti-oxidants, most of which will disappear dur-ing the industrial process (‘curing’, roasting) and be replaced by often large amounts of AGE/ALE. As the temperature increases above 130°C, carcinogens, especially hetero-cyclic amines, will also be produced, and their production increases dramatically as the tem-perature increases. AGE/ALE will not exclu-sively reach the body through the food we eat, or the smoke we inhale – they are also produced spontaneously in the body, espe-cially in the presence of increased levels of sugars and fatty acids in body fluids and tis-sues, and in those suffering chronic diseases such as diabetes and chronic renal diseases.

22.4 AGE/ALE Accumulation in the Body

The accumulation of late/matured Maillard products – AGE/ALE – in the body is in prin-ciple irreversible; what is accumulated in the tissues persists for a very long time and most often forever. Hitherto, the finding of larger amounts of AGE/ALE in the tissues of elderly individuals has simply been regarded as a

normal effect of ageing. However, it might not be so. Instead it might mainly be a result of the lifestyle chosen, smoking, and eating habits, and thus in theory preventable. Large to extreme increases in AGE/ALE are regularly observed in body fluids and tissues of patients with chronic diseases, particularly those with diabetes and chronic renal diseases, and in patients suffering complications of these dis-eases. It is commonly observed in diabetic patients, who suffer from reduced wound healing (Peppa et al., 2003), retinopathy, neph-ropathy (Zheng et al., 2002), and angiopathy (Vlassara et al., 2002; Lin et al., 2003). Accumulation of AGE/ALE in tissues is seen as intracellular or extracellular deposits referred to as tau proteins, amyloid b proteins (Smith et al., 1994), and in neurofibrillary tan-gles (Smith et al., 1994; Vitek et al., 1994). Such depositions in various body tissues were long regarded as degenerative but biologically inert structures. However, increasing evidence sup-ports the conclusion that these structures are foci with very strong pro-inflammatory poten-tial, which maintain the systemic chronic inflammation at a high level in the tissues, and thereby accelerate further production of AGE/ALE and exacerbation of disease.

22.5 Modern Molecular Biology: Essential for Understanding the Effects

of AGE/ALE

Almost 100 years ago, Maillard suggested that accumulation in the body of AGE/ALE would significantly contribute to the progression of diseases, especially of chronic urinogenital diseases, and in particular uraemia. He created what he called an ‘index of urinogenital imper-fection’, which he used to document the asso-ciation between the degree of accumulation in the body of Maillard products and the severity of disease, especially chronic renal disease.

The time was, however, not opportune for such radical thinking, and the concept was largely ignored by scientists and clinicians of the time, remaining so for several decades to come. It was the introduction of modern molec-ular biology and particularly the identification of specific receptors in the body for these



substances that would dramatically change the attitude and interest in these substances by both biologists and physicians. The turning point seems to be the identification in 1992 by the American Ann Marie Schmidt of a specific receptor for AGE/ALE named RAGE (Schmidt et al., 1992, 1993, 1994a,b). Since then increasing numbers of publications have appeared in the literature. From the year 2000, several interna-tional scientific organizations have become involved in the concept, arranging special sym-posia on RAGE and AGE/ALE, and publish-ing special issues relating to these topics. New societies have also been founded with the aim of specifically investigating the effects of food-derived AGE/ALE on health and well-being. The New York Academy of Science seems to have taken the lead and many scientific contri-butions on AGE/ALE are published each year in its Annals. Searches on PubMed relating to AGE and ALE reveal more than 5000 publica-tions, of which more than 25% appeared in 2009. In addition almost 20,000 titles on PubMed are about glycated haemoglobin, HbA1c.

Several methods are available for the measurement of content of AGE/ALE in body fluids and tissues: immunohistochemistry with polyclonal or monoclonal antibodies, high per-formance liquid chromatography (HPLC), and mass spectrography. A majority of these sub-stances are auto-fluorescing even if not visible to the human eye, and so can be used for diag-nostic purposes (Meerwaldt et al., 2005a,b). The fluorescence has its maximum at wavelengths between 350 and 440 nm (Meerwaldt, 2005b). Often-studied substances such as CML and CEL do not, unfortunately, show any fluoresc-ing ability, nor do they have any colour. Despite this, measuring fluorescence is an excellent tool for clinical use, especially for screening of indi-viduals with suspected high levels of AGE/ALE in the body, but also for screening of foods suspected to be rich in such dysfunctional proteins.

22.6 RAGE: a Master Switch and Key to Inflammation

RAGE is a prominent member of what has been called the immunoglobulin superfamily of cell-surface molecules. It is described as a

‘master switch’ with the ability to coordinate the inflammatory reaction in the body. RAGE induces a long-lasting activation of the pro-inflammatory transcription factor NF-kB and suppresses a series of endogenous auto-regu-latory functions (Schmidt et al., 2001; Bierhaus et al., 2001, 2005a; Vlassara, 2005). Increased deposition of AGE/ALE in the tissues is sug-gested to be a key element in the develop-ment of the so-called metabolic syndrome (Koyama et al., 2005; Soldatos et al., 2005). Accumulation of AGE/ALE and subsequent activation of RAGE is reported to induce a significant down-regulation of leptin in adi-pose cells (Unno et al., 2004). RAGE activation induces effects on a great variety of tissues, but they are particularly pronounced in endothelial cells, where increased expression occurs of a long row of molecules such as VCAM-1, ICAM-1, E-selektin, eNOS, and TGF-b. TNF-a, Il-6, PAI-1, and VEGF are seen (Bohlender et al., 2005). Strong RAGE-induced effects are often observed on immune cells, macrophages (Sunahori et al., 2006), and den-dritic cells (de Leeuw et al., 2005; Ge et al., 2005), but also on smooth muscle, particularly in the walls of blood vessels, under the mucosa and in the skin (Aronson, 2003). These changes are associated with subsequent reduction in regenerative capacity and func-tion of the cells, increased blood pressure, and development of chronic diseases and/or exacerbation of complications to chronic dis-eases (Monnier et al., 2005). However, the con-ditions vary from tissue to tissue, the most sensitive and vulnerable being those with low regenerative capacity and long-lived cells such as myelin- and collagen-rich structures, where the substances are likely to remain. Among these are brain, peripheral nerves, skeleton, muscles, tendons, joints, skin, and eye, especially the lens.

Research in recent years has also demon-strated the existence of an endogenous solu-ble form of RAGE known as sRAGE, which has an important effect as a decoy for RAGE and has been shown to prevent accumulation of RAGE in body tissues (Bierhaus et al., 2005b). This suggests that chronic diseases are not only associated with increased levels of RAGE in the body, but also, and probably as important, with low levels of sRAGE.


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22.7 Factors Underlying Enhanced Systemic Inflammation

The largest part of the immune system is, in contrast to what was earlier believed, to be found in the gastrointestinal (GI) system (Brandtzaeg et al., 1989) as 70–80% of the Ig-producing cells are located within the GI tract. This explains why the food we eat has such a profound influence on our well-being and health. Although AGE/ALE seem to play a major role, it is also clear that numerous other food-related factors will influence the degree of systemic inflammation in the body, the sensitivity to develop disease and our daily well-being. Increasing evidence sug-gests that all these factors are additive and collectively contribute to development of a sustained, long-lasting, often discrete and unrecognized, exaggerated stage of inflam-mation in the body, commonly seen before and when a chronic diseases is manifest. Such factors are:

• Low vitamin D status. There is a strong correlation between the level of vitamin D in the body, degree of inflammation and incidence of chronic diseases. Individuals living at higher latitudes such as Canada, Russia, and Scandinavia, but also countries in the Southern hemi-sphere, such as Argentina, New Zealand, and Uruguay are reported to have gener-ally lower levels of vitamin D in serum, especially during the winter season. This phenomenon is associated with higher incidence of coronary–vascular diseases, acute coronary events (Zittermann et al., 2005; McCarty, 2005) and other chronic diseases such as cancer (Mohr et al., 2006, 2007, 2008).

• Low levels in the body of antioxidants such as folic acid and glutathione, and increased lev-els of homocysteine. Increase in serum lev-els of homocysteine is regularly associated with increased levels of systemic inflam-mation and chronic diseases (Mattson, 2003).

• Impaired hormonal homeostasis. Ageing as well as chronic diseases are commonly accompanied by hormonal disturbances of various kinds, sometimes to the extent

that ageing has been referred to as a state of ‘hormonal chaos’ (Hertoghe, 2005). Hormonal disturbances are often accom-panied by increased oxidative stress/increased release of free radicals, intracel-lular accumulation of ‘waste products’, inhibition of apoptosis, disturbed repair mechanisms, reduced gene polymor-phism, premature shortening of telomeres, and reduced immune defence. Reduced resistance to disease is often observed in premature ageing as well as in several chronic diseases (Hertoghe, 2005). In par-ticular, 17b-estradiol, plentiful in dairy products, is known to induce a strong acti-vation of RAGE mRNA in endothelial cells. This effect is abolished if an anti-oes-trogen such as 4-OH tamoxiphen is sup-plied (Yamagishi et al., 1998, Suzuma et al., 1999). An impaired hormonal homeostasis is suggested to explain why chronic dis-eases are often aggravated during preg-nancy, frequently seen as vascular and eye complications to diabetes (Suzuma et al., 1999). Physical as well as mental stress also contributes to activation of RAGE, and increased release of noradrenaline is reported to reduce immune defence and increases sensibility to acquire infections by up to 4 logs (Cooper, 1946). Increased release of noradrenaline in the intestine will dramatically reduce the beneficial intestinal flora, and increase the virulence of potentially pathogenic micro-organisms (Kinney et al., 2000; Alverdy et al., 2003), changes, which most likely also contribute to increased RAGE activation. Permanently increased levels of noradrenaline are reported in chronic diseases such as Alzheimer’s disease and also found to cor-relate well with severity of the disease (Peskind et al., 1998). Parathyroid hor-mones constitute another example of hor-mones deeply involved in the inflammatory process. Significant elevations in IL-6 are observed in hyperparathyroidism as in other chronic conditions with increased systemic inflammation such as obesity (Flyvbjerg et al., 2004).

• Angiotensin/renin. Oxidative stress and increased systemic inflammation is also strongly associated with increased release



of angiotensin, increased levels of free fatty acids in serum, and with reduction in beta-cell function in diabetes (Flyvbjerg et al., 2004; Tikellis et al., 2006; Allen et al., 2005). The observation that blockage of the angiotensin receptor will reduce pro-duction and accumulation of AGE both in vitro and in vivo is of great interest (Allen et al., 2005).

• Larger intake of glutenoids. Glutenoids are increasingly regarded as pro- inflammatory in the body (Tlaskalová-Hogenová et al., 2005), and suggested to occur even in the absence of intestinal changes (Brady and Hoggan, 2002; Sbarbati et al., 2003).

• Low intake of plant antioxidants.• High intake of carbohydrates.• High intake of saturated and trans fatty

acids. A strong association is repeatedly documented between the average con-tent of fat in food and morbidity and/or mortality in chronic diseases in a coun-try, as demonstrated for breast cancer (Carroll, 1975), as well as other cancers and also chronic diseases such as coro-nary heart disease (Artaud-Wild et al., 1993; Moss and Freed, 1999) and diabetes (Dahl-Jorgensen et al., 1991). More than three quarters of the saturated fat con-sumed is of bovine origin, and thus it is not surprising that the incidence of vari-ous chronic diseases also correlates well with the amount of dairy products con-sumed (Ganmaa et al., 2002).

22.8 Dietary Choice

The incidence of most chronic diseases has increased dramatically during the last 150 years, much of it in parallel with the signifi-cantly altered intake of foods which has occurred since the year 1850: a doubling of intake of saturated fat, 50% reduction in intake of omega-3 fatty acids, and a more than doubling in intake of omega-6 fatty acids (Leaf and Weber, 1988). The intake of refined sugar has during the same time period increased from approximately 0.5 kg to about 50–60 kg per person per year. Furthermore, the transition in use to carbohydrates with

stronger pro-inflammatory effects such as high-fructose corn syrup (HFCS), seems to make the situation even worse. In the United States, the intake of HFCS in carbonated drinks and fast foods now exceeds that of sucrose (Gaby, 2005).

A recent study in mice is of particular interest. Over 4 months, RAGE knock-out (KO) mice received either a standard diet (7% fat) or a Western ‘fast-food’-like diet (21% fat) and were compared to wild-type mice, receiving the same diet. The Western-food-like diet was associated with significant cardiac hypertro-phy, inflammation, mitochondrial- dependent superoxide production, and accumulation of AGE in both strains, but significantly less in the RAGE-KO mice. Both strains demonstrated reduced levels of inflammation and oxidative stress, in association with reductions in AGE as well as RAGE on supply of an AGE inhibitor (alagebrium chloride, 1 mg Kg−1 day−1 (Tikellis et al., 2008).

Much can be learnt from studies of Japan, which has during the last 50–60 years made similar, although not as extensive, changes in food habits as the West. The incidence of sev-eral chronic diseases has increased dramatically during this time. As an example, the incidence of prostate cancer has increased 25-fold during the last 50 years, much in parallel to an increase in the consumption of industrially produced agricultural foods: 7 times more eggs, 9 times as much meat, and 20 times as much dairy product (Ganmaa et al., 2002, 2003).

22.9 Dairy in Focus

Commonly, 10–20% and sometimes up to 70% of the amino acid lysine is reported to be mod-ified during the common industrial treatment of milk (including sterilization, pasteuriza-tion, and irradiation). Fructoselysine is the dominating modified molecule, but CML and pyrraline are also produced during the processing of milk. Sugar content, the level and time of elevated temperature, and storage time are the main factors behind the increased production of AGE/ALE in milk products.

Not only the industrial treatment of dairy products but also the feeds given to the cows


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have changed dramatically during the 20th century – from mainly forage-based to starch-rich and fast-absorbed carbohydrates such as corn, maize grains, barley, molasses, and dex-trose. Intensive feeding of cows with carbo-hydrates induces insulin resistance in animals as well as in humans. Should the animals be allowed to live long enough they would also show the same symptoms of Western diseases including manifest diabetes. It has been dem-onstrated that milk- and lactose-fed calves show signs of insulin resistance at a young age (Hostettler-Allen et al., 1994).

High levels of pro-inflammatory cytokines and various stress hormones are regularly observed in intensively fed animals. No infor-mation is available in the literature, however, to support the notion that elevated inflamma-tory molecules are transferred to humans by meat and dairy products from such animals. Today’s dairy products come, much in contrast to the old days, up to about 80%, from preg-nant cows, and consequently are rich in growth factors and various hormones, especially sex hormones (Malekinejad et al., 2006), some of which (like 17b-oestradiol) are potentially pro-inflammatory and carcinogenic. It is suggested that dairy-derived hormones and growth fac-tors are important pathogenetic factors behind the development of hormone-dependent can-cers, especially of the colon, prostate, and breast (Outwater et al., 1997). These hormones follow the fat fraction and are thus more con-centrated in condensed products such as but-ter, cheese, and powdered milk.

It has been demonstrated that vegans, in great contrast to meat-eaters and lacto- vegetarians, have lower levels of AGE/ALE. Lacto-vegetarians seem to have even higher levels of AGE/ALE than meat-eaters (Sebekova et al., 2001), which might be explained by a higher intake of dairy products, especially cheese, to compensate for not eating lean meat, but which might also be due to a higher intake of fructose. Significant health advantages are reported for vegans: lower levels of pro-inflammatory molecules, cytokines and acute phase proteins; lower systolic and diastolic blood pressure; lower total cholesterol; lower LDL-cholesterol; lower fasting blood sugar and triglycerides; and lower incidence of chronic diseases, especially diabetes and complications

to diabetes (Barnard et al., 2009). It would be no surprise if the lowest levels of AGE/ALE are to be found in the group referred to as raw-eaters, especially if they avoid dairy-based foods, but unfortunately, this group has attracted few studies and none with regard to the content of AGE/ALE.

22.10 AGE/ALE and Disease

Increased accumulations of AGE/ALE in tis-sues have been reported in numerous chronic diseases, as detailed below. In addition, changes in the skin and oral cavity may serve as markers of health risks associated with AGE/ALE.

22.10.1 Allergy and autoimmune diseases

Thermal processing, curing, and roasting of foods are known to often increase allergenic-ity of pre-existing allergens and also to intro-duce new antigens. Sometimes, however, reduced allergenicity has been reported (Davis et al., 2001; Sancho et al., 2005). Common foods such as milk, peanuts, and soy are reported to induce significant increases in AGE levels and to severely affect the IgE-binding capacity (Chung et al., 2001; Franck et al., 2002; Rautava and Isolauri, 2004). Significantly elevated urinary levels of the AGE pentosine are observed in allergic chil-dren in association with signs of exacerbation of atopic dermatitis (Tsukahara et al., 2003).

22.10.2 Alzheimer’s disease and other neurodegenerative disease

Alzheimer’s disease (AD) is one of the most common chronic diseases, affecting approxi-mately 5% of all individuals over 65 years of age and more than 35% of those over 80. Strong similarites exist between AD and type 2 diabetes (T2DM), to the extent that Alzheimer’s has been called ‘the diabetes of the brain’, or type 3 diabetes. The incidence of AD is reported to to be increased two- to fivefold in TD2DM (Nicolls, 2004). An approximate threefold



increase in content of AGE is observed in AD brains compared to age-matched controls (Moreira et al., 2005). A common feature of both diseases is accumulation of amyloid deposits, a process which progresses during the course of disease, and much relates to the stage of disease. Signs of amyloidosis, pertu-bation of neuronal properties and functions, amplification of glial inflammatory response, increased oxidative stress, increased vascular dysfunction, increased Ab in the blood–brain barrier, and induction of autoantibodies are regularly seen. Increased levels of AGE and signs of oxidative damage are almost regularly observed in the eyes, known to be early targets of AD (Moreira et al., 2005). Central to, if not the cause of AD, is the progressive oligomeri-zation and deposition in the cells of amyloid b-peptides (Ab), tau, prions, and transthyretin, all glycated molecules with strong neurotoxic effects. Amyloid b-peptides accumulate extra-cellularly to form amyloid plaques, while tau protein deposits occur as neurofibrillary tan-gles within the cells. Increased levels of AGE/ALE are most often demonstrated with immu-nohistochemical methods in senile plaques, tau proteins, amyloid b proteins, and in neu-rofibrillary tangles (see below (Vitek et al., 1994; Moreira et al., 2005)). Accumulation of AGE/ALE in brain tissues has also been observed in Parkinson’s disease (PD) (Castellani et al., 1996; Dalfo et al., 2005), and cytoplasmic proteinaceous inclusions com-posed of the protein a-synuclein (a-syn) and named Lewy bodies are regularly observed in PD. AGE/ALE are also implicated in the pathogenesis of other neurodegenerative dis-eases: amyotrophic lateral sclerosis (ALS) (Chou et al., 1998; Kikuchi et al., 2002; Kaufmann et al., 2004), Huntington’s disease (Ma and Nicholson, 2004), stroke (Zimmerman et al., 1995), familial amyloidotic polyneuropathy (Gomes et al., 2005), and Creutsfeldt-Jakob dis-ease (Sasaki et al., 2002). Early accumulation of AGE is also reported in Down’s syndrome, and early antiglycation treatment is suggested to reduce cognitive impairments (Odetti et al., 1998; Thiel and Fowkes, 2005). It has also been suggested that bovine spongiform encepha-lopathy (BSE) a disease with its significant similarities to AD, might be associated with increased glycation and lipoxidation

(Frey, 2002). Involvement of glycation prod-ucts and activation of prion proteins are also suggested by other authors (Boratynski and Gorski, 2002; Choi et al., 2004). AGE, amyloid fibrils, and prions all seem to have the same target, RAGE, and all activate the NF-kB path-way. Interaction between RAGE and Ab is most likely to be the most important implica-tion in the development of AD, enhancing inflammation in blood vessel endothelium, inducing increased response of NF-kB, medi-ating transport of Ab across the blood–brain barrier, suppressing cerebral blood flow, and inducing cell death (apoptosis). RAGE is known to mediate Ab-induced migration of monocytes across the thin brain endothelium and into the brain tissues.

Increased cholesterol is suggested to con-tribute to the production of AD by increasing generation of beta-amyloid (Ab), and animal studies suggest that cholesterol co-localizes with fibrillar Ab in the amyloid plaques (Burns et al., 2003).

22.10.3 Atherosclerosis and other cardiovascular disorders

Oxidative stress, lipid peroxidation, and pro-tein glycation are repeatedly associated with extensive arteriosclerosis. Significant increases in both chemical AGE (carboxymethyllysine) and fluorescent AGE (spectrofluorometry) were observed in 42 patients with atheroscle-rosis when compared to 21 healthy controls (p<0.001) (Kalousova et al., 2005). Increased levels of malondialdehyde, lipid peroxides, and pentosidine were seen in a study of 225 haemodialysis patients and these also corre-lated significantly with the degree of coronary artery calcifications (Taki et al., 2006). Significant lipid oxidation, deposition of AGE/ALE in the arterial walls, and development of atheroscle-rosis, are reported in rabbits fed a diet contain-ing 1% cholesterol. Deposition is further enhanced when 10% fructose is added to the diet (Tokita et al., 2005). Structural modifica-tions of high density lipoproteins (HDL), lipoxidation, glycation, homocysteinylation, or enzymatic degradation will make HDL lose its anti-inflammatory and cyto-protective abil-ity (Ferretti et al., 2006). This emphasizes its


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importance in the pathogenesis of arterioscle-rosis, as in neurodegenerative diseases, diabe-tes, and other autoimmune diseases (de Leeuw et al., 2005). Supplementing AGE-modified serum albumin to experimental animals will significantly increase secretion of pro-inflam-matory cytokines, maturation of dendritic cells, and augment the capacity to stimulate T-cell proliferation (Ge et al., 2005). The AGE CML in plasma was followed for six years in 1270 people aged 65 and older. In this period, 227 (22.4%) died during the period, 105 in car-diovascular disease. This mortality was sig-nificantly associated with high CML levels (Semba et al., 2009).

22.10.4 Cancer

Individuals with high levels of oxidative stress, such as those with type 2 diabetes and significantly increased accumulation in the body of AGE/ALE, suffer a significantly increased risk of developing cancer (Abe and Yamagishi, 2008). The receptor RAGE and its multiple ligands are shown to be involved in the pathogenesis of multiple tumours: brain, breast, colon, colorectal, lung, prostate, oral squamous cell carcinoma, and ovarian cancer, as well as lymphoma and melanoma (Takada et al., 2004; Genkinger et al., 2006; Logsdon et al., 2007). In vitro and animal studies, as well as preliminary clinical observations, sup-port the view of a direct link between RAGE activation and proliferation, migration, inva-sion of tumour cells, and survival (Logsdon et al., 2007; Abe and Yamagishi, 2008). RAGE expression is reported to be elevated in human cells with high metastatic ability and low in tumour cells with low metastatic abil-ity (Takada et al., 2004). A tumour-suppressive function of RAGE has also been reported for some distinct cell types (Gebhardt et al., 2008). It is suggested that cytokines produced by cells of the innate immune system play an indispensable role in tumour-promoting inflammation, while protective anti-tumour effects derive largely from adaptive immune cells, particularly T cells (Dougan and Dranoff, 2008). An up-regulation of the gene S100P, known to be involved in the activation of RAGE, has been reported for several

tumour tissues including lung, breast, pan-creas, prostate, and colon (Rehbein et al., 2008). The RAGE ligand sRAGE, highly expressed in healthy lung tissues especially at the site of alveolar epithelium, is significantly down-regulated in lung carcinomas (Jing et al., 2010), but also in pancreatic cancer (Krechler et al., 2010). The relationship between RAGE expression in surgical speci-mens of primary tumours and prognosis of the patient was studied recently in 216 patients with oesophageal squamous cell car-cinoma (Tateno et al., 2008). Those with posi-tive RAGE expression in tumour cells exhibited a significantly better prognosis than those with negative RAGE expression (5-year survival, 52% versus. 32%, respectively) (Tateno et al., 2008).

22.10.5 Cataract and other eye disorders

AGE/ALE accumulate with age in all ocular tissues including lacrimal glands, and trigger pathogenic events, especially in diabetics, in all parts of the eye (Stitt, 2005). The lens con-tains abundant proteins, which undergo translational modifications throughout the lifespan, contributing to ageing and cataract formation. Kynurenines are diffusible com-ponents of the lens that absorb UVA and UVB radiation, and are believed to protect the ret-ina from light damage. However, it is also unstable under physiological conditions and undergoes deamination, its half-life being approximately 7 days. The deaminated prod-ucts, known to affects lens proteins and mod-ify specific amino acids, are believed to contribute to AGE formation, ageing of the lens, and to development of cataracts (Nagaraj et al., 2010). Age-related macular degenera-tion (AMD) is also strongly associated with increased oxidative stress, and with increased deposition of AGE/ALE. A recent study found signs of systemic AGE accumulation in patients with AMD, implicating a role for AGE/ALE in the pathophysiology of AMD (Mulder et al., 2010). The AGE CML and pen-tosidine are also shown to be significantly increased in AMD patients relative to healthy controls: CML (∼54%), and pentosidine (∼64%) (p < 0.0001) (Ni et al., 2009). RAGE and



its ligands are also reported to be involved in retinal diseases (Barile and Schmidt, 2007) and in glaucoma (Tezel et al., 2007).

22.10.6 Diabetes

More than 6000 publications in PubMed deal with AGE/ALE and more than half of them particularly with their role in diabetes melli-tus (DM). Several excellent reviews have been published recently (Meerwaldt et al., 2008; Orasanu and Plutzky, 2009; Yan et al., 2009). Over-consumption of fat and carbohydrates, not only of glucose, but also of other carbohy-drates such as lactose and fructose, contribute in diabetics to a significantly increased accu-mulation of AGE/ALE in the tissues. The con-sumption of high-fructose corn syrup in the United States today exceeds that of sucrose. It is ten times more capable of producing AGE/ALE, and is suggested as a major contributor, not only to obesity and accumulation of fat in the liver, but specifically to development of type 2 diabetes as well as to severe complica-tions of both type 1 and 2 diabetes (Gaby, 2005). Chronic hyperglycaemia is suggested to alter mitochondrial function through glyca-tion of mitochondrial proteins. A direct rela-tionship is demonstrated between excess intracellular formation of reactive species, intracellular formation of AGE from mitochon-drial proteins, and decline in mitochondrial function (Rosca et al., 2005). Methylglyoxal (MGO), a highly reactive a-dicarbonil by-product of glycolysis, which readily reacts with arginine, lysine, and sulfhydryl groups of both proteins and nucleic acids to form AGE, is significantly increased in diabetes (Ceriello, 2009). Diabetic complications such as retinopathy, nephropathy, and neuropathy are significantly associated with levels of AGE in the body. Increased levels of AGE in skin biopsies are found to be significantly associ-ated with the outcome of micro-vascular com-plications (Genuth et al., 2005), and closely associated with incidence and severity of dia-betic complications.. Intensive control of gly-caemia in insulin-dependent diabetes (IDDM) effectively delays the onset and slows down the progression of diabetic retinopathy, neph-ropathy, and neuropathy (DCCT, 1993). Five

years of such treatment will significantly reduce various AGE/ALE in the body (30–32% lower furosine, 9% lower pentosidine, 9–13% lower CML), and increase the levels of soluble collagen (24% higher in acid-soluble collagen, and 50% higher in pepsin-soluble collagen) (Monnier et al., 1999).

22.10.7 Endocrine disorders

Many, if not most, of the signs and symptoms of ageing, and age-associated diseases are strongly associated with multiple hormone deficiencies. Most consequences of ageing, such as excessive free radical formation, imbalance of the apoptosis systems, failure of repair systems, tissue accumulation of waste products, deficient immune system, poor gene polymorphisms, and premature tel-omere shortening, are all associated, if not caused, by hormone deficiencies (Hertoghe, 2005). Up-regulation of putative pathological pathways, accumulation of advanced glyca-tion end products, activation of the renin–angiotensin system, oxidative stress, and increased expression of growth factors and cytokines are all intimately associated with ageing. However, little information is yet available about the content of AGE/ALE in endocrine organs and their influence on the body both in health or disease. With the exception of the ovaries, most of the endo-crine organs – the pituitary gland, thyroids, parathyroids, adrenals, and testes – are thus far almost totally unexplored. Increased serum AGE levels and increased activation of RAGE are reported in women with poly-cystic ovary syndrome (PCOS) (Diamanti-Kandarakis et al., 2005). A recent study reports that the content of AGE/ALE is twice as high in patients with PCOS as in healthy controls, and also strongly associated with signs of increased chronic inflammation; increases in homocysteine (Hcy), malonyldialdehyde (MDA), C-reactive protein (CRP), and with higher fasting insulin levels; and a higher homeostasis model assessment (HOMA) index (fasting glucose (mg dl−1) x fasting insu-lin (mU ml−1) x 0.055/22.5) (Kaya et al., 2009). Deposition of excess collagen in PCOS tis-sues that induce cystogenesis are suggested,


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at least in part, to be due to stimulation by AGE (Papachroni et al., 2009).

22.10.8 Gastrointestinal disorders

Various gastrointestinal cancers and their ability ot grow and produce metastases are associated to increased levels of AGE/ALE in the body and to increased activity of RAGE. Little, however, is known about an eventual association between accumulation in the body of these molecules or activity of RAGE and common inflammatory and ulcerative conditions in the gut. The only exception seems to be a recent study, which reports that the urinary concentration of pentosidine is significantly elevated in active compared to inactive IBD, ulcerative colitis (0.12 versus 0.021 mg mg−1), and Crohn’s disease (0.071 versus 0.039 mg mg−1) (Kato et al., 2008).

22.10.9 Liver disorders

Patients with liver cirrhosis demonstrate much increased AGE levels, which sometimes reach almost the same extent as in patients with end-stage renal disease (Sebekova et al., 2002). Serum levels of AGE (CML) are shown to be significantly affected by the stage of the disease in liver cirrhosis, and are closely asso-ciated with liver function capacity, as reported in a study 110 patients with chronic liver dis-ease (CLD) and compared to 124 healthy con-trols (Yagmur et al., 2006). Furthermore, the level of AGE (CML) seemed to correlate well with levels of hyaluronic acid (HA) (r = 0.639, P < 0.0001). Glyoxal-derived adducts are sug-gested to be increased up to no less than 15 times in both portal and hepatic venous plasma of cirrhotic patients compared to healthy controls (Ahmed et al., 2005). A dra-matic improvement is observed in patients after liver transplantation, although the AGE levels do not return to the levels seen in healthy controls (Sebekova et al., 2002). Animal studies suggest that blockage of RAGE is highly protective against hepatocellular necro-sis and cell death, and to significantly increase the rate of survival (Zeng et al., 2004; Ekong

et al., 2006). A significant increase in glutath-ione and pro-regenerative cytokines TNF-a and IL-6 are observed, in addition to decreased hepatic necrosis and increased survival (Ekong et al., 2006). Much remains to be done to define the role of AGE/ALE and RAGE in the pro-gression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and cirrhosis. However, recent obser-vations of serum glyceraldehyde-derived AGE levels (U ml−1) being significantly ele-vated in NASH patients (9.78) compared to those with simple steatosis (7. P = 0.018) and healthy controls (6.96, P = 0.003) are of signifi-cant interest (Hyogo et al., 2007). These authors also observed an inverse correlation to the level of adiponectin, an adipocytokine with insulin-sensitizing and anti-inflammatory properties. Immunohistochemistry of glycer-aldehyde-derived AGE also showed increased staining in the livers of NASH patients.

22.10.10 Lung disorders

A variety of airway diseases such as asthma, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), cystic fibrosis, and idiopathic pul-monary fibrosis are all characterized by lack of homeostasis in the oxidant/antioxidant balance. Interaction of AGE/ALE and RAGE are well known to play a large, if not domi-nating, role in the depletion of antioxidants, particularly reducted glutathione (GSH) in lung epithelial lining and to play a key role in the pathogenesis of these disorders (Foell et al., 2003; Rahman et al., 2006a).

22.10.11 Rheumatoid arthritis and other skeletomuscular disorders

Among the highest levels of AGE in the body, and the strongest expression of RAGE, are found in inflamed tissues characterized for slow turnover, such as tendons, bone, carti-lage, skin, and amyloid plaques. These changes are associated with a slight change in colour towards yellow-brown and and an increased fluorescence, all associated with



increased expression of pro-inflammatory cytokines and matrix metalloproteinases (MMP), especially MMP-1 and MMP-9. These manifestations are regarded as being respon-sible for the observed increased tissue stiff-ness and brittleness in structures such as intervertebral discs, bones, tendons, carti-lages, synovial membranes, and skeletal mus-cles, and are regarded as major pathogenic factors behind diseases such as osteoarthritis (DeGroot, 2004; Steenvoorden, 2006), rupture of inter-vertebral discs (Hormel and Eyre 1991), rupture of Achilles tendons (Reddy, 2004), menisci, and also in rheumatoid dis-eases (Hein et al., 2005; Sunahori, et al., 2006), such as rheumatoid arthritis (Matsumoto et al., 2007) and fibromyalgia (Hein and Franke, 2002; Rüster et al., 2005). A significant increase in glycation of myosin occurs with age (Ramamurthy et al., 2001), and is most likely to contribute to age-associated muscu-lar disorders. High levels of AGE/ALE in the body are also reported in patients with oste-oporosis; significantly elevated levels of pen-tosidine and CML in serum (Hein et al., 2003) and significantly increased pentosidine in cortical bone (Odetti et al., 2005) being observed. It has also been observed that the remodelling of senescent bone is impaired by AGE, with both stimulation of bone-resorbing cytokines and enhancement of bone resorp-tion by osteoclasts being observed (Miyata et al., 1996). A recent American study reports a significantly reduced bone density in older women consuming > 3 cola drinks per week when compared to matched controls consum-ing similar amounts of other carbonated soft drinks (Tucker et al., 2006). This information is especially interesting when one considers that cola drinks, much in contrast to other soft drinks, are considered rich in AGE. A recent in vitro study reports profound effects by cola-derived AGE: activation of platelets, an up to 7.1-fold increase in CD62 expression, and an increase of up to 2.2-fold in CD63 at the plate-let surface membrane, also accompanied by increases in RAGE expression (Gawlowski et al., 2009).

The common belief that bovine milk pre-vents osteoporosis is today much questioned. Instead, increasing documentation suggests that it has quite the opposite effects, and that

negative interactions of RAGE and AGE/ALE play a larger role in the pathogenesis of osteoporosis than lack of minerals.

22.10.12 Skin and oral cavity issues

The skin is one of, if not the largest, organ in the body. The health condition of the skin has a similar ability to the gingiva in the mouth, to reflect the total health of the body. Skin autoflu-orescence seems to be a good measure of cumulative metabolic stress and accumulation of advanced glycation end products in the body (Meerwaldt et al., 2005a,b). Accumulation of AGE/ALE in the skin relates to the content of these proteins in the body, and so is an expression of the risk of developing chronic diseases, in particular coronary heart disease. A recent study found a significant correlation between coronary calcifications and AGE/ALE in the body measured as skin fluores-cence, suggesting such measurements could serve both as a marker of risk but also as a measurement of therapeutic success when patients are treated (Conway et al., 2010). Skin autofluorescence is especially suggested to be a method for prediction of the risk for progres-sion of diabetic complications such as angiop-athy, nephropathy, and retinopathy, and the severity of disease and mortality in haemodi-alysis patients (Meerwaldt et al., 2005b).

The skin has a high density of RAGE receptors. AGE/ALE are known to accumu-late in dermal elastine and in collagens, and to interact with dermal fibroblasts, inhibit-ing their proliferation capacity. A tenfold reduction in proliferation rate is described to occur normally in humans from the second to seventh decade (Stamatas et al., 2006), and is suggested as explaining the reduced heal-ing capacity of age-related wounds, and especially chronic wounds, such as those on the diabetic foot. RAGE and AGE/ALE-induced apoptosis and enhanced loss of fibroblasts and osteoblasts are also regarded as major pathogenic factors in periodontal pathology, especially in chronic periodonti-tis (Holla et al., 2001). A 50% increase is observed compared with controls in RAGE mRNA in gingiva of diabetic patients (p<0.05) (Katz et al., 2005).


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22.10.13 Urogenital disorders

Nephropathy is today more common than ever before and continues to increase, much in parallel to the increase in diabetes. It is the single most important cause of end-stage renal failure in the western world (Ostergaard et al., 2005). Consequently it s receives great interest from scientists. Today no less than 1000 papers in PubMed deal with RAGE and AGE/ALE in renal diseases. Diabetic neph-ropathy today affects 15–25% of patients with type 1 diabetes, and as much as 30–40% of patients with type 2 diabetes. The kidney appears as both culprit and target of AGE/ALE, and it is well documented that RAGE is significantly activated, and advanced AGE/ALE markedly elevated in renal failure patients. Patients with mild chronic ure-mic renal failure are reported to have plasma glycation-free adduct concentrations increased up to fivefold, patients with end-stage renal disease as much as 18-fold when on peritoneal dialysis, and up to 40-fold on haemodialysis (Agalou et al., 2005). A decrease in renal function and reduced clearance is observed much in parallel to increases in cir-culating AGE levels. AGE are involved in the structural changes observed in progressing nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy (Bohlender et al., 2005). For detailed informa-tion, see recent excellent reviews (Vlassara et al., 2009; Daroux et al., 2010; Schepers et al., 2010). Kidney transplantation is reported to improve but does not fully correct the increased AGE/ALE levels in previously dialysed patients.

22.11 Foods Rich in AGE/ALE

It is a most interesting observation that increased accumulation of AGE/ALE in endothelial cells, and most likely also in some other tissues, can be significantly avoided or reduced by control of intake of foods known to contain these substances in large amounts. Thus far the information regarding content of AGE/ALE in foods is rather incomplete. Leading universities around the world are

building institutions for studies of nutragen-omics (how various food ingredients affect our health). However, from existing informa-tion it is clear that dysfunctioning proteins are especially rich in foods which have been subjected to industrial processing. The foods with the highest AGE content were animal-derived products exposed to high, dry heat such as broiling, frying, and grilling. A detailed description of the database can be found in Goldberg et al. (2004). A brief sum-mary is provided below.

• Heated dairy products: powdered milk (ice cream, baby and clinical nutrition formu-las) cheese, especially when heated. High in pizza, tacos, nachos, salads, fast food, sandwiches, sauces, and brown cheeses.

• Heated grain products: bread (e.g. toasted bread, bread crusts, and crispbreads).

• Heated meat, poultry, and fish: especially bacon, sausages, fried, and barbecued meat. The content of AGE/ALE increases as one goes from boiling to oven frying: boiling (1000 kU/serving) < roasting (4300 kU) < broiling (5250 kU) < deep fry-ing (6700 kU) < oven frying (9000 kU/serving) (Goldberg et al., 2004).

• Other heated foods: egg yolk powder, leci-thin powder, coffee (especially dark roasted), hard-cured teas, roasted and salted peanuts, dark and sugar-rich alco-holic beverages, broth, Chinese soy, balsamic vinegar, cola drinks, etc.

A recent study adds further and impor-tant information about dietary AGE (Uribarri et al., 2010). It should be observed that lean red meats and poultry contain high levels of die-tary AGE. Even when cooked under dry heat, the explanation is that among the intracellular components of lean muscle there are highly reactive amino lipids, as well as reducing sug-ars such as fructose or glucose-6-phosphate. In the presence of heat, this combination rapidly accelerates new AGE formation (Uribarri et al., 2010). The highest AGE levels are observed in beef and cheeses followed by poultry, pork, fish, and eggs, while lamb ranked relatively low in AGE, at least when compared to other meats. Cheeses, butter, and different types of oils are AGE-rich, even in uncooked forms. High-fat spreads, including butter,



cream cheese, margarine, and mayonnaise, are also among the foods containing the highest AGE, followed by oils and nuts. It should especially be observed that olive oil, for exam-ple, contains large amounts of AGE when heated to 100°C for 5 min (Uribarri et al., 2010). Carbohydrate-rich foods such as vegetables, fruits, and whole grains contain relatively few AGE, even after cooking (Uribarri et al., 2010).

22.12 Prevention and Treatment of AGE/ALE Accumulation

22.12.1 Changing food preparation habits

It is clear that significant benefits will be obtained by reducing the intake of cheese, meats, powdered milk, other processed foods such as heated oils, and also of bread; and instead increase the consumption of vegeta-bles and fruits, especially when raw. These rec-ommendations are in line with the policy of various expert organizations with the aim to reduce chronic diseases such as cancer, heart diseases, and hypertension (cancer: American Cancer Society, 2006; heart: Lichtenstein et al., 2006; hypertension: US Department of Health and Human Services et al., 2006). AGE forma-tion in food is reduced when cooking on sur-faces that provide no direct contact with metal; when foods are immersed in acid solutions such as tomato sauce and ketchup; and when there is contact with aminoguanidine, a known inhibitor of AGE formation (He et al., personal communication, 2010). Eating foods raw or prepared at a low temperature (below 80°C), steam cooking or boiling, and minimal cook-ing are preferred over frying, grilling, and microwaving, and also to roasting and salting. Recent information seems especially to warn against microwaving food, as this treatment dramatically accelerates the rate of AGE pro-duction (Visentin et al., 2010). A trial designed to compare the potential metabolic effects of two different diets, one based on mild steam cooking and another based on high- temperature cooking was recently reported (Birlouez-Aragon et al., 2010). A randomized crossover study assigned 62 volunteers (university students) to each of the two diets

for four weeks. Consuming the steamed-cooked diet for 1 month induced significantly improved insulin sensitivity and also increased plasma levels of omega-3 fatty acids (217%, p = 0.002), vitamin C (213%, p = 0.0001), and vitamin E (28%, p = 0.01), in comparison to the high temperature diet. Furthermore, reduced concentrations of plasma cholesterol (5%, p = 0.01) and triglycerides (9%, p = 0.01) were also reported.

A challenge for the future in the Western world is to find techniques to produce bread at 100°C or below as the Chinese have done for centuries. Marinating for some hours at room temperature with ingredients such as antioxi-dant-rich herbs, garlic, tea, red wine, onions, olive oil, and beer are also known to signifi-cantly reduce the development of AGE/ALE, and this was also recently demonstrated for heterocylic aromatic amines (Melo et al., 2008). Reduction in total intake of proteins (Uribarri and Tuttle, 2006), and most likely a particular reduction in methionine and other sulphur-containing amino acids, are additional issues of relevance (McCarty et al., 2009).

22.12.2 Energy restriction

Significant reduction in body content of AGE/ALE in comparison to controls (eating stand-ard Western food) is observed in individuals, who for > 2 years practise what is called caloric restriction (CR). They eat only two thirds of what they would like to, and this is accompa-nied by significant health advantages com-pared to matched controls: lower blood pressure (102/61±7 versus 131/83 mm Hg), and lower levels of markers of inflammation such as CRP (0.3 versus 1.9 mg l), TNF-a (0.8 versus 1.5 pg ml−1), and TGF-b (29.4 versus 35.4 ng ml−1) (Meyer et al., 2006). Elevated RAGE and low sRAGE is reported in patients with active rheumatoid arthritis (RA), but patients with RA practising CR for about 2 months demonstrated not only lower levels of pentosidine (an often-measured AGE) in urine, but also lower disease activity (Iwashige et al., 2004). Thirty-seven obese individuals (mean BMI of 28.3 ± 3.2) were treated with calorie restriction for 8 weeks. Reduction occurred in BMI (6.3%, p < 0.001), waist


396 S. Bengmark

circumference (5.7%, p < 0.002), triglycerides (11.9 % (p < 0.002), and AGE (7.21%, p < 0.001) (Gugliucci et al., 2009). FEV1, an expression of respiratory capacity, almost doubled.

22.12.3 Antioxidants and vitamins

Provision of vitamins such as A, B (especially B6 and B12), C, D, E, and K, as well as glutath-ione and folic acid, is often emphasized. Many plant antioxidants, particularly those collec-tively defined as polyphenols, have docu-mented oxidation-quenching properties up to ten times more powerful than conventional vitamins. They have also been shown to have great chemo-preventive properties, a marked ability to prevent accumulation in the body of AGE/ALE, and significant capacities to reduce inflammation in the body and to prevent reduction in organ function and premature ageing (Delmas et al., 2005; Osawa and Kato, 2005; Bengmark, 2006; Rahman et al., 2006b; Sun et al., 2010). Such plant antioxidants exist in nature in many thousands – most probably hundreds of thousands – of different com-pounds. More than 4000 flavonoids alone have been identified, and almost 1000 carotenoids. Here are the most studied: isothiocyanates in cruciferous vegetables; anthocyanins and hydroxycinnamic acids in cherries; epigallo-catechin-3-gallate (EGCG) in green tea; chloro-genic acid and caffeic acid in fresh coffee beans and also in fresh tobacco leaves; capsaicin in hot chilli peppers; chalcones in apples; euginol in cloves; gallic acid in rhubarb; hisperitin and naringenin in citrus fruits; kaempferol in white cabbage; myricetin in berries; rutin and quer-cetin in apples and onions; resveratrol and other procyanidin dimers in red wine and vir-gin peanuts; various curcumenoids, the main yellow pigments in turmeric curry foods; and daidzein and genistein from the soy bean.

22.12.4 Supplementing histidine, taurine, carnitine, or carnosine

Supplementing the diet with histidine, tau-rine, carnitine, or carnosine has also been reported to assist in protecting the body from

AGE/ALE (Nandhini et al., 2004, 2005). No vegetarian food contains taurine, with the exception of certain algae. This important amino acid is only obtained from eating ani-mal-derived foods – meat, poultry, and fish.

22.12.5 Pharmaceuticals

Several pharmaceuticals, especially those used for treatment of diabetes, are reported to reduce the content of AGE/ALE in the body, at least in short-lived tissues; that is, those with high turnover.

22.13 Pro- and Synbiotics

Probiotics and synbiotics have a dual role in reduction of dietary AGE/ALE as they both metabolize these substances (Erbersdobler et al., 1970; Finot and Magnenat, 1981; Faist and Erbersdobler, 2001; Faist et al., 2001, Wiame et al., 2002) and also release important vitamins and antioxidants with documented preventive effects against AGE and ALE. A rich intestinal flora is regarded as necessary for the release and absorption of various important antioxidants. However, the increased intake of refined food and deficient intake of fresh fruits and vegetables among Westerners has led to a significant reduction in both density and diversity of the flora. This reduction is especially pronounced for strong fibre-fermenting lactic acid bacteria (LAB) such as Lactobacillus plantarum and Lb. paraca-sei. Seventy-five per cent of omnivorous Americans and 25% of vegetarians in the United States lack Lb. plantarum (Finegold et al., 1983). A more recent Scandinavian study found Lb. plantarum in only 52% and Lb. paracasei in only 17% of healthy individuals (Ahrné et al., 1998). This information is partic-ularly interesting, as Lb. plantarum and Lb. paracasei belong to the small group of intesti-nal bacteria with ability to break down semi-resistant fibres such as inulin (Müller and Lier, 1994), reduce inflammation, reduce infection, and eliminate pathogenic bacteria such as Clostridium difficile (Naaber et al., 2004). Some specific LAB might well have the ability to



eliminate AGE/ALE from foods, in a way that is very similar to that demonstrated for gluten (di Cagno et al., 2005) and heterocyclic amines (Tavan et al., 2002). In vitro studies have shown that fructoselysine, the dominating AGE in heated milk, can be effectively eliminated when incubated with fresh intestinal flora (Erbersdobler et al., 1970).

22.14 Conclusions

There is growing consensus that the dietary intake or endogenous production of AGE/ALE is associated with a diverse range of dis-orders, although the underlying mechanisms remain largely obscure. This chapter has focused on the dietary sources of AGE/ALE and on the effects of heat treatment in the pro-duction of these dysfunctional adducts during the processing of foods. The accumulation of AGE has been documented in conditions such as Alzheimer’s disease, cardiovascular disease, cancer, diabetes, lung disease, liver disease, and other disorders, and this research evidence has also been reviewed in this chapter.

It is increasingly clear that the intestinal microflora and its more than 2 million meta-genes play a key role in health and disease. Western lifestyle is clearly associated with a deranged microbionta, with reduced diversity and an increased quotient between gram- negative and gram-positive bacteria, which in association with reduced barrier function seems to contribute to the observed elevated systemic inflammation. Patients with meta-bolic derangements such as obesity and with chronic diseases are known to have increased blood levels of endotoxin, a product of gram-negative bacteria. Recent in vitro observations suggest that human AGE-modified albumin

and lipopolysaccharide (LPS) exhibit a syner-gistic effect on proinflammatory cytokine/chemokine interleukin-6, interleukin-8, and monochemoattractant protein-1 production in human endothelial cells (Liu et al., 2009). A link exists between fat intake and accumulation of endotoxin in the blood (endotoxaemia), and recent studies demonstrate that intake of emul-sified fat in particular (water-in-oil emulsions such as butter; free oil or dispersed fat inclu-sions in cheeses, cookies, ice cream, and dress-ings), which is known to affect the kinetics of lipid absorption, increases both endoxaemia and inflammation (Laugerette et al., 2010).

It is now well documented in the litera-ture that a healthy lifestyle has profound effects on health and well-being. Control of what we eat is an important component within such a programme. Studies suggest reductions of as much as 83% in coronary heart disease (Stampfer et al., 2000), 91% in diabetes (Hu et al., 2001), and 71% in colon cancer (Platz et al., 2000) in patients adhering to a ‘healthy lifestyle’ (such as no use of tobacco, moderate use of alcohol, regular physical exercise, and controlled food intake). To these four factors must be added control of stress. Numerous studies demonstrate that both physical and mental stress increases the degree of inflammation in the body and acti-vates RAGE (Kjaer, 2004; Bierhaus et al., 2006; Chida et al., 2006). Control of intake and endogenously produced AGE/ALE, will, together with restrictions on the intake of fat and carbohydrate-rich foods, significantly improve health and well-being. However, only a fraction of consumers are willing to consider this option. A study in the United States (Reeves and Rafferty, 2005), suggests that only about 3% adhere to the principles advocated above.

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104. Acid-based etc In D´Mello handbook 2011

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